The role of calmodulin and calmodulin-dependent protein kinases in the pathogenesis of atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory disease that triggers severe thrombotic cardiovascular events, such as stroke and myocardial infarction. In atherosclerotic processes, both macrophages and vascular smooth muscle cells (VSMCs) are essential cell components in atheromata formation through proinflammatory cytokine secretion, defective efferocytosis, cell migration, and proliferation, primarily controlled by Ca 2+ -dependent signaling. Calmodulin (CaM), as a versatile Ca 2 + sensor in diverse cell types, regulates a broad spectrum of Ca 2+ -dependent cell functions through the actions of downstream protein kinases. Thus, this review focuses on discussing how CaM and CaM-dependent kinases (CaMKs) regulate the functions of macrophages and VSMCs in atherosclerotic plaque development based on literature from open databases. A central theme in this review is a summary of the mechanisms and consequences underlying CaMK-mediated macrophage inflammation and apoptosis, which are the key processes in necrotic core formation in atherosclerosis. Another central theme is addressing the role of CaM and CaMK-dependent pathways in phenotypic modulation, migration, and proliferation of VSMCs in atherosclerotic progression. A complete understanding of CaM and CaMK-controlled individual processes involving macrophages and VSMCs in atherogenesis might provide helpful information for developing potential therapeutic targets and strategies.

miRNA‑92a inhibits vascular smooth muscle cell phenotypic modulation and may help prevent in‑stent restenosis

“…in a previous study, chen (12) reported that the recruitment of smooth muscle cells into the intima of the vessel wall was a significant contributor to atherosclerotic plaque progression. Moreover, VSMcs within the medial layer of the vessel wall were then activated to migrate and proliferate in response to iSr (12). a previous study suggested that the Kruppel-like factor (KlF) family serves a vital role in homeostasis maintenance within the body, including in the immune, digestive, respiratory, hematopoietic and cardiovascular systems (13).…”

“…Similar to numerous evolutionarily conserved miRNA-92a inhibits vascular smooth muscle cell phenotypic modulation and may help prevent in-stent restenosis processes, these properties can also be considered a disadvantage and predispose patients to various abnormal responses after injury, which contribute to restenosis (8). in a previous study, chen (12) reported that the recruitment of smooth muscle cells into the intima of the vessel wall was a significant contributor to atherosclerotic plaque progression. Moreover, VSMcs within the medial layer of the vessel wall were then activated to migrate and proliferate in response to iSr (12).…”

Involvement of protein kinases associated signal transduction mechanisms in cardiac diseases

“…It is also pointed out that PI3K plays an important role in the regulation of leukocyte recruitment, monocyte migration, reactive oxygen species production, and endothelial cell apoptosis [101]. More specifically, the isoform PI3Kγ primarily controls leukocyte infiltration in the myocardium and arteries, which is a key factor in atherosclerosis [102]. Inhibition of PI3K, on the other hand, can weaken endocytic clearance mechanisms leading to increased plaque necrosis, inflammatory response, and more vascular vulnerabilities [102].…”

“…More specifically, the isoform PI3Kγ primarily controls leukocyte infiltration in the myocardium and arteries, which is a key factor in atherosclerosis [102]. Inhibition of PI3K, on the other hand, can weaken endocytic clearance mechanisms leading to increased plaque necrosis, inflammatory response, and more vascular vulnerabilities [102]. Several studies have also demonstrated that calmodulin and CaMKs contribute to the development of atherosclerosis, and suppressing calmodulin or CaMKs with inhibitors or genetic manipulation has been shown to alleviate atherosclerotic severity [103].…”